3-alkoxy-17alpha-alkynyl-16, 16-difluoroestra-1, 3, 5(10)-trien-17beta-ols



3,054,808 3-ALKOXY-17a-ALKYNYL16,16-DIFLUOR0-ESTRA-1,3,5(l)-TRIEN-17B-0LS Arthur H. Goldkamp, Glencoe, 111., assignorto G. D.

Searle & Co., Chicago, 111., a corporation of Delaware No Drawing. FiledOct. 3, 1960, Ser. No. 59,791 2 Claims. (Cl. 260397.5)

The present invention is concerned with novel 16,16- difiuorinatedsteroids and, more particularly, with 3- alkoxy 17oa-alkynyll6,l6-difluoroestra-l,3,5(10)-trien- 17 8-ols of the structural formulaon eson wherein R is hydrogen or a lower alkyl radical and R is a loweralkyl radical.

Lower alkyl radicals encompassed by R and R are, typically, methyl,ethyl, propyl, butyl, pentyl, hexyl, and the branched-chain isomersthereof.

The instant compounds can be manufactured by treating the appropriate 3alkoxy 16,16 difluoroestral,3,5,( 10)-trien-l7-one (prepared by thedifluorination of the corresponding 3-alkoxyestra-l,3,5(l0-trien-17-oneaccording to the procedure described in my copending application, SerialNo. 843,058, filed September 29, 1959, of which the present applicationis a continuation-inpait) with a lower l-alkyne, for example in liquidammonia in the presence of lithium amide. Alternatively, the 17-ketonecan be condensed with the appropriate alkynyl lithium reagent. A thirdmethod involves the addition of the alkynyl magnesium halide to theappropriate l7-ketone under the conditions of the Grignard reaction. Aprocedure particularly suitable for the manufacture of the compounds inwhich R in the structural representation supra is a lower alkyl radical,involves the conversion of a 17a-ethynyl-17fl-ol of this invention toits Grignard derivative, then alkylation of the latter substance withthe appropriate alkyl halide.

The compounds or" this invention are useful as intermediates in themanufacture of the corresponding 17ozalkyl derivatives, which may beobtained by catalytic hydrogenation of these intermediates. The instantcompounds are useful also in view of their valuable pharmacologicalproperties, particularly as exemplified by their ability to reduce theserum concentration of cholesterol and the correspondingcholesterol/phospholipid ratio without at the same time producing thepotent feminizing side effects characteristic of known estrogens adaptedto the regulation of cholesterol metabolism.

The invention will appear more fully from the examples which follow.These examples are set forth by way of illustration only and it will beunderstood that the invention is not to be construed as limited inspirit or in scope by the details contained therein, as manymodifications in materials and methods will be apparent from thisdisclosure to those skilled in in the art. In these examplestemperatures are given in degrees centigrade C.). Quantities ofmaterials are expressed in parts by weight unless otherwise noted.

EXAMPLE 1 To a mixture of 0.1 part of ferric nitrate monohydrate and2,000 palts of liquid ammonia is added, portionwise, 11 parts oflithium. When the blue color has disappeared, acetylene is bubbledthrough the mixture for about 45 minutes. To this suspension is thenadded 3.2 parts of 16, 1 6-difiuoro-3-methoxyestra- 1,3,5 10)-trien-17-one, andthe resulting mixture is stirred for about 5 hours.The ammonia is then allowed to evaporate, and the residue is treatedsuccessively with ether and saturated aqueous To a mixture of 4.3 partsof lithium wire and parts of ether, under nitrogen, is added dropWiseover a period of about 30 minutes, a solution of 34.25 parts of n-butylbromide in 35 parts of ether While the temperature is kept at 10. Thisreaction mixture is stirred at 010 for about one hour, then filteredunder nitrogen to aflord 154 parts by volume of an ethereal solution ofbutyl A mixture of 51 parts by volume of the aforementioned etherealbutyl lithium solution with 35 parts of ether is cooled to l0, thentreated dropwise, over a period of about 30 minutes, with a solution of6 parts of butyne-l in 35 parts of ether. The resulting mixture istirred at 0 for about 1 /2 hours. The cooling bath is removed, andthere is then added dropwise to this mixture a solution of 12.6 parts of3-n-butoxy-16,l6-difluoroestra-l,3,5(10)-trier1-17-one in parts oftetrahydrofuran. After the addition is complete, the solvent isdistilled, keeping the volume constant by the addition oftetrahydrofuran. When the temperature of the distillate reaches 55, thedistillation is stopped, and the mixture is heated at reflux for about 3hours, then cooled, and poured slowly into ice Water. The oily productwhich forms is separated by decantation, then dissolved in ether. Theethereal solution is washed successively with water and saturatedaqueous sodium chloride, dried over anhydrous sodium sulfate, andconcentrated in vacuo to afford 3 n butoxy l7a-butynyl 16,16difluoroestra- 1,3,5 l0) -trien-l7;8-0l.

What is claimed is:

l. A compound of the structural formula wherein R is selected from thegroup consisting of hydrogen and lower alkyl radical and R is a loweralkyl radical.

2. 17a-ethynyl-16,16-difiuoro-3-methoxyestra-1,3,5(10)- t1i6I1-17j3-0l.

No references cited.

1. A COMPOUND OF THE STRUCTURAL FORMULA